2-amino-alpha-substituted-benzylideneamines and methods for making the same



United States Patent 3,513,191 Z-AMINO-a-SUBSTITUTED-BENZYLIDENEAMINESAND METHODS FOR MAKING THE SAME Stanley C. Bell, Penn Valley, Pa.,assignor to American Home Products Corporation, New York, N.Y., acorporation of Delaware No Drawing. Original application July 25, 1963,Ser. No. 297,705. Divided and this application Aug. 8, 1966, Ser. No.572,646

Int. Cl. Ctl7c 101/44; C07d 63/12 US. Cl. 260-518 6 Claims ABSTRACT OFTHE DISCLOSURE 2-aminobenzylideneamines are prepared by cleavage of1,3-dihydro-2H-l,4-benzodiazepin-2-ones. The cleavage products arepharmacologically active.

vention may be administered parenterally or orally in conventionaldosage forms such as tablets, powders, injectables, etc.

The compounds of the invention are represented by the following generalformulae:

NAB i O=NZ Y vir and wherein: X and Y are selected from the groupconsisting of hydrogen, halogen, nitro, lower alkyl, preferably havingup to 9 carbon atoms in the chain and halo(1ower) alkyl having up to 2carbon atoms such as trifiuoromethyl; A is selected from the groupconsisting of hydrogen, lower alkyl, lower acyl, halo(lower) acyl andaralkyl having up to 7 carbon atoms; B is hydrogen or lower alkyl; Z isa radical selected from the group consisting of (lower) alkyl, loweraralkyl, hydroxy(lower) alkyl, alkoxyalkyl, dialkoxyalkyl, mercaptoalkyl, in which the alkyl and alkoXy groups have up to 2 carbon atoms,aminoalkyl having up to 7 carbon atoms, carboxyalkyl having up to 2carbon atoms, acyloxyalkyl having up to carbon atoms, and alkylthioalkylhaving up to 3 carbon atoms; W is a member selected from the groupconsisting of the lower alkyl and aryl radicals such as methyl, phenyl,2- furyl, or Z-thienyl. Compounds where W is phenyl substi- 3,513,191Patented May 19, 1970 tuted by halogen, lower alkoxy, lower alkyl, orhalo- (lower)alkyl are full equivalents of the subject matter to bepatented.

The compounds of the invention may be prepared by methods illustratedschematically below wherein the substituents have the significance abovenoted, R is hydrogen, lower alkyl or aryl and M is an alkali metalcation, such as sodium, lithium, potassium, rubidium and cesium. F isthe same as Z except that it does not represent carboxyalkyl oracyloxyalkyl.

METHOD I A 6 t t X r-o H X N-o H OH- \R R Y CN C=N l -L W W 0 (III) (IV)X A X A I IH -I IH 0 I O1 7 C=NCHRCO0M (|3==NCHRCOOM Y v v Y w METHOD IINAB 1 fr X o-w NAB I A -C=NF X Y Y \ll (VII) (I) NAB ii-W NAB X FNHOH TC| =NF Y Y W (VII) (II) In Method I, ring cleavage between the one andtwo positions of a 1,3-dihydro-2H-1,4benzodiazepin-2-one or -2-one4-oxide is etfected by treating with dilute alkali metal hydroxide toyield the alkali metal salt of a substituted 2amino-a-substituted-benzylideneaminoacetic acid or of its N-oxide,respectively. Acidification of the N -oxide yields the free imino acid,N-oxide.

The starting products used in Method I may be prepared by known methods.One such method comprises acylating a Z-aminophenyl ketone with anot-chloroacyl chloride to give a 2-(a-chloroacylamino) phenyl ketonewhich undergoes ring closure when treated with alcoholic ammonia to forma 1,3-dihydro-2H-1,4-benzodiazepin-2- one. Another synthesis of thestarting materials comprises the condensation of a Z-aminophenyl ketonewith hydroxylamine to form its corresponding oxime. The resultingaminophenyl ketone oxime is then acylated with an a-haloacyl halide toform the corresponding haloacylamino oxime, which undergoes ring closureunder acid conditions to form a 2-(a-haloalkyl)-quinazoline 3-oxide.Treatment of this compound with a strong base results in ringenlargement with the formation of a 1,3-dihydro-2H-1,4-benzodiazepin-2-one 4-oxide.

In Method II, which is suitable for the preparation of a wider number ofcompounds than Method I, an appropriately substituted phenone iscondensed by heating with a suitably substituted primary amine.Optionally, Method II may be carried out in an inert solvent such asXylene,

toluene or hexanol and if desired, with a catalytic amount of an acidcatalyst such as Zinc chloride or toluene-sulfonic acid. Upon cooling,water is added to the mixture to precipitate the product which can bepurified by crystallizing from a water-alcohol mixture and then from abenzene-hydrocarbon mixture. In the special case where the amine reagentis benzylamine, the product is ordinarily a mixture ofN-(2-amino-5-chloro-a-phenylbenzylidene) benzylamine and of itstautomer, N-(2-arnino-5-chloroa-phenylbenzyl) benzaldehyde imine.

Method III is identical with Method II except that a substitutedhydroxylamine is used instead of a primary amine.

Methods II and III lead to the possible production of two geometricisomers (c and forms) because of the formation of a carbon-nitrogendouble-bond. Where both isomers are stable and isolable, the presentinvention naturally comprehends both forms. Separation of the afrom thefi-isomers can be achieved by known techniques, such as fractionalcrystallization.

The following specific examples in which all temperatures are in degreescentigrade serve to illustrate the invention.

Example 1 A solution of 2.0 g. of 7-chloro-1,3-dihydro-1-methyl- 95-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide in 15 ml. of ethanol, 15 ml.of water and 15 ml. of N sodium hydroxide solution is warmed for severalminutes. The resultant sodium salt is filtered, dissolved in water andthe free acid precipitated out by the addition of acetic acid.Recrystallization from acetonitrile gave 5-chloro-2-methylamino-a-phenylbenzylideneaminoacetic acid N-oxide, M.P. 150-1(dec.).

The analytical data confirmed the empirical formula The N-oxide soobtained is converted back to 7-chloro 1,3-dihydro-l-methyl-S-phenyl 2H1,4-benzodiazepin- 2-one-6-4-oxide by treatment with hot, aqueousalcoholic hydrochloric acid.

Example 2 By following the procedure of Example 1, 7-ch1oro- 1,3-dihydro5 phenyl-ZH-l,4-benzodiazepin-2-one 4- oxide is converted to 2amino-S-chloro-int-phenylbenzylidene aminoacetic acid N-oxide, M.P.151-2.

Analysis.--Calcd for C H ClN O /2H O (percent): C, 57.42; H, 4.50; N,8.93; Cl, 11.30; H O, 2.87. Found (percent): C, 57.57; H, 4.57; N, 9.14;CI, 11.40; H O, 2.7.

This compound was converted to the sodium salt, M.P. 2202.

Analysis.Calcd for C H ClN O Na (percent): N, 8.57; Cl, 10.85. Found(percent): N, 8.57; Cl, 10.74.

The 2 amino-5-chloro-u-phenylbenzylideneaminoacetic acid N-oxide isconverted back to 7-chloro-1,3-dihydro- 5-phenyl2H-1,4-benzodiazepin-2-one 4-oxide by treatment with aqueous alcoholichydrochloric acid.

Example 3 By following the procedure of Example 1,7-chlorol,3-dihydro-5-phenyl 2H 1,4-benzodiazepin-2-one is converted tothe sodium salt of 2-amino-5-chloro-a-phenylbenzylideneaminoacetic acid,M.P. 218.

Analysis.-Calcd for C H ClN O Na (percent): CI, 11.41; Na, 7.40; M.W.316.73. Found (percent): Cl, 11.50; Na, 7.50.

On treatment with cold dilute acid, this compound is converted back to7-chloro-1,3-dihydro-5-phenyl-2H-1,4- benZodiazepin-2-one with someaccompanying hydrolysis to 2-amino-5-chlorobenzophenone and glycine.

Example 4 By following the procedure of Example 1, 7-chloro- 1,3-dihydro1 methyl-S-phenyl-ZH-1,4-benzodiazepin-2- 4 one is converted to thesodium salt of 5-chloro-2-methylamino-a-phenylbenzylideneaminoaceticacid, M.P. 265.

Analysis.Calcd for C H ClN O Na (percent): N, 8.63; Cl, 10.92. Found(percent): N, 8.44; CI, 10.70; M.W. 324.75.

Example 5 A mixture of 3.0 g. of Z-amino-5-chlorobenzophenone and 30 ml.of ethanolamine is refluxed for 4 hours. Upon cooling, the reactionmixture is diluted with water and the product that separates isrecrystallized from wateralcohol and then benzene-cyclohexane to givepure 2-(2- amino-5-chloro-a-phenylbenzylideneamino) ethanol, M.P.122-124.

Analysis.--Calcd for C H ClN O (percent): C, 65.56; H, 5.50; N, 10.20;Cl, 12.90; M.W. 274.75. Found (percent): C, 65.55; H, 5.44; N, 10.40;Cl, 12.90.

Example 6 3-aminopropanol is reacted with Z-amino-S-chlorobenzophenone,according to the procedure in Example 5, to give3-(2-amino-S-chloro-a-phenylbenzylideneamino) propanol, M.P. 107-109.

Analysis.-Calcd for C H CIN O (percent): C, 66.50; H, 5.92; N, 9.70.Found (percent): C, 66.26; H, 5.96; N, 9.66.

Example 7 3-morpholinopropylamine is reacted with2-methylamino-5-chlorobenzophenone according to the procedure of Example5 to give 4-[3-(2-methylamino-5-chloro-aphenylbenzylideneamino propyl]morpholine.

Example 8 2-ethoxyethylamine is reacted with 2-amino-5-ethylbenzophenoneaccording to the procedure of Example 5 to give2-(2-amino-5-ethyl-oc-phenylbenzylideneamino) ethoxyethane.

Example 9 2-(2 amino 5 nitro-a-phenylbenzylideneamino) ethoxy-ethane isreacted with acetic anhydride in pyridine to give2-(2-acetamido-5-nitro-a phenylbenzylideneamino) ethoxyethane.

Example 10 Ethanolamine is reacted with2-amino-5-trifluoromethylbenzophenone according to the procedure ofExample 5 to give2-(2-amino-5-trifiuoromethyl-a-phenylbenzylideneamino)ethanol.

Example 11 2-amino-5-chlorophenyl-2-thienyl ketone is reacted with2-2-morpholinoethylamine according to the procedure of Example 5 to give4-(-[2-amino-5-chloro-a-(Z-thienyl) benzylideneamino]ethyl)morpholine.

Example 12 2-amino-5-chlorobenzophenone is reacted with 3-phenethylamine according to the procedure of Example 5 to give1-(Z-amino-5-chloro-a-phenylbenzylideneamino) -2-phenylethane.

Example 13 2-amino-5-chlorobenzophenone is reacted with 2-aminoethanethiol according to the procedure of Example 5 to give2-(2-amino-5-chloro-a-phenylbenzylideneamino)ethanethiol.

Example 14 A solution of3-(2-amino-5-chloro-a-phenylbenzylideneamino)propanol in pyridine wastreated with acetic anhydride and the reaction mixture then diluted withWater. The resultant precipitate was filtered giving 3-(2-acetamido-S-chloro a phenylbenzylideneamino)propyl acetate, M.P.122-124".

Analysis.-Calcd for C H ClN O (percent): C, 64.42; H, 5.81; N, 7.52; Cl,9.51. Found (percent): C, 64.77; H, 5.73; N, 7.79; Cl, 9.70.

Example Z-amino-2',S-dichlorobenzophenone was reacted with ethanolamineaccording to the procedure of Example 5 to give2-[2-arnino-5-chloro-u-(o-chlorophenyl)benzylideneaminoJethanol, M.P.123-125 Analysis.Calcd for C H Cl N O (percent): C, 58.27; H, 4.56; N,9.06; Cl, 22.93. Found (percent): C, 58.54; H, 4.62; N, 9.25; C1, 22.70.

Example 16 2-methylamino-5 chlorobenzophenone was refluxed withethanolamine and the resultant reaction mixture poured into water. Theaqueous phase was decanted from the resultant insoluble oil and this oilwas washed several times with water, then dissolved in ether and theether solution was dried and the ether removed in vacuo leaving aviscous oil, 2-(Z-methylamino-S-chloro-a-phenylbenzylideneamino ethanol.

Analysis.-Calcd for CleHlqClNgO (percent); C, 66.54; H, 5.94; N, 9.70.Found (percent): C, 66.23; H, 5.75; N, 10.09.

Example 17 2-amino-5-chlorobenzophenone was reacted with benzylamineaccording to the procedure of Example 5 to giveN-(2-amino-5-chloro-a-phenylbenzylidene)benzylamine, M.P. l22-124 andits tautomer N-(2-amino-5- chloro-a-phenylbenzyl)benzaldehyde imine.

Analysis.-Calcd for C H CIN (percent): C, 75.89; H, 5.34; N, 8.74; Cl,11.07. Found (percent): C, 74.80; H, 5.44; N, 8.93; C1, 11.10.

Example 18 2-benzylamino-5 chloroacetophenone is reacted withethanolamine according to the procedure of Example 5 to give2-(2-benzylamino 5 chloro-1x-methylbenzylideneamino) ethanol.

Example 19 S-bromo-2-dimethylaminobenzophenone is reacted with2,2-diethoxyethy1amine according to the procedure of Example 5 to give2-(5-bromo-2-dimethylamino-a-phenyL benzylideneamino-1,1-diethoxyethane.

Example 20 A solution of 23.1 g. of 2-amino-5-ch1orobenzophenone and 45g. of 4-(2-aminoethyl)morpholine in 100 ml. of xylene and a catalyticamount of zinc chloride was refiuxed for 3 hours until the theoreticalamount of water had separated out. The solvent was removed in vacuo andthe residue recrystallized from heptane and then ethanol giving thea-isomer of N-[2-(2-amino-5-chloro-a-phenylbenzylideneamino) ethyl]morpholine, M.P. 140-142 Analysis.-Calcd for C H ClN O (percent): C,66.36; H, 6.45; Cl, 10.32; N, 12.22. Found (percent): C, 66.13; H, 6.29;Cl, 10.40; N, 12.09.

The above heptane filtrate was concentrated to a small volume and thesolid that precipitated out was recrystallized from cyclohexane and thenalcohol-water giving the B-form of N-[2(2-amino-5-chloro-u-phenylbenzylideneamino)ethyl]morpholine, MP. 112-114C.

AnaZysis.-Calcd for C H ClN O (percent): C, 66.36; H, 6.45; Cl, 10.32;N, 12.22. Found (percent): C, 66.17; H, 6.50; Cl, 10.35; N, 12.4.

Example 21 2-amino-5-chlorobenzophenone was reacted with 4-(3-aminopropy1)morpholine according to procedure of Example 20 to give theocand fl-isomers of N-[3-(2-amino- S-chloro-a-phenylbenzylideneaminopropyl] morpholine.

Analysis.Calcd for C H ClN O (percent): C, 67.12; H, 6.76; Cl, 9.90; N,11.75. a-Isomer, M.P. 91- 92 Found (percent): C, 67.23; H, 6.76; Cl,9.84; N,

6 11.94. ,B-Isomer, M.P. 118-119F0und (percent): C, 67.36; H, 6.79; Cl,9.94; N, 11.85.

Example 22 Example 23 2-(2-amino 5 chloro-a-phenylbenzylideneamino)-ethanol was reacted with acetic anhydride according to the procedure ofExample 14 to give 2-(2-acetamido-5-clloro-a-phenylbenzylideneamino)ethyl acetate, M.P. 99- 1 1.

Analysis.Calcd for C H ClN O (percent): C, 66.55; H, 4.10; N, 10.35.Found (percent): C, 66.45; H, 4.03; N, 10.55.

Example 24 N-[3-(2-ch1oroacetamido) 5 chloro-u-phenylbenzylipropyl]morpholine was reacted with chloroacetic anhydride according to theprocedure of Example 14 to give N-[3-(2-chloroacetamido) 5chloro-a-phenylbenzylideneamino) propyl]morpholine, M.P. 107-109.

Analysis.-Calcd for C H Cl N O (percent): C, 60.83; H, 5.80; Cl, 16.33;N, 9.67. Found (percent): C, 60.92; H, 5.85; Cl, 16.30; N, 9.44.

Example 25 N-[2-(2-amino-5 chloro-a-phenylbenzylideneamino)ethyl]morpholine was reacted with acetic anhydride according to theprocedure of Example 14 to give N-[2-(2- acetamido 5chloro-a-phenylbenzylideneamino)ethyl]- morpholine, MP. l47-149 C.

Analysis.Calcd for C H C1N O (percent): C, 65.30; H, 6.27; Cl, 9.19; N,10.89. Found (percent): C, 65.34; H, 6.13; Cl, 9.30; N, 10.73.

Example 26 3.5 g. of2-(2-acetamido-5-chloro-a-phenylbenzylideneamino)ethyl acetate wasdissolved in a solution of 5 ml. of 4 N sodium hydroxide and 50 ml. ofethanol. The solution was diluted with water and the solidrecrystallized from carbon tetrachloride giving2-(2-acetamido-5-chloroot-phenylbenzylideneamino)ethanol, M.P. 143-145Analysis.Calcd for C1 7H17C1Nz02 (percent): C, 64.45; H, 5.41; Cl,11.19; N, 8.84. Found (percent): C, 64.60; H, 5.39; Cl, 11.20; N, 8.92.

Example 27 Reacting 2 amino 5-chlorophenyl-2-furyl ketone andmethylthioethyl-amine according to Example 5 affords 2- [2-amino-5chloro-a-(2 furyl)-benzylideneamino]-1- methylthioethane.

Example 28 Following the procedure of Example 1, 7,8-dimethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide is converted to2-amino-4,5-dimethyl-a-phenylbenzylideneaminoacetic acid N-oxide.

It will be understood that many changes and variations may be effectedin the preparative methods of the invention without departing from thespirit and scope thereof.

7 What is claimed is: 1. A compound selected from the group consistingof and represented by the formulae:

1 X (N-H Y C=N-CHR o o OM and i X N-H Y C=NCHRC o OM in which X and Yare members of the group consisting of hydrogen, chlorine, bromine,nitro, lower alkyl and trifiuoromethyl, A is a member of the groupconsisting of hydrogen, lower alkyl and lower alkanoyl, W is a member ofthe group consisting of phenyl, thienyl and phenyl substituted by amember of the group consisting of chlorine and methyl while R is amember of the group consisting of hydrogen or lower alkyl and M isselected from the group consisting of hydrogen and an alkali metalcation.

2. As a compound of claim 1;2-amino-5-chloro-rxphenylbenzylideneaminoacetic acid.

3. As a compound of claim 1;5-chloro-2-methylaminoa-phenylbenzylideneaminoacetic acid.

4. As a compound of claim 1;2-amino-5-chl0ro-uphenylbenzylideneaminoacetic acid N-oxide.

5. As a compound of claim 1;5-chloro-2-methylamino-a-phenylbenzylideneaminoacetic acid N-oxide.

6. The process which comprises treating with an alkali metal hydroxide acompound selected from the group consisting of and represented by theformula:

8 and A X I l-0:0

l x R Y C=N wherein X and Y are members of the group consisting ofhydrogen, nitro, halogen, lower alkyl and ha1o(lower) alkyl; A is amember of the group consisting of hydro-.

gen, lower alkyl and aralkyl; W is a member of the group consisting oflower alkyl, monocyclic aryl, thienyl and furyl; R is a member of thegroup consisting of hydrogen, lower alkyl and monocyclic aryl, to form acompound of the group consisting of and represented by the formulae:

wherein A, R, W, X, and Y are as hereinbefore stated and M is the cationof an alkali metal hydroxide.

References Cited UNITED STATES PATENTS 3,154,578 10/1964 Kinnel et a1.260-518 LORRAINE A. WEINBERGER, Primary Examiner L. ARNOLD THAXTON,Assistant Examiner US. Cl. X.R.

